Cord blood–derived T cells allow the generation of a more naïve tumor‐reactive cytotoxic T‐cell phenotype

Abstract

BACKGROUND Transplantation of hematopoietic stem cells (HSCs) from peripheral blood (PB) or cord blood (CB) is well established. HSCs from CB are associated with a lower risk of graft‐versus‐host disease (GVHD), but antigen‐independent expanded CB‐ and PB‐derived T cells can induce GVHD in allo‐HSC recipients. CB‐derived cells might be more suitable for adoptive immunotherapy as they have unique T‐cell characteristics. Here, we describe functional differences between CB and PB T cells stimulated with different cytokine combinations involved in central T‐cell activation. STUDY DESIGN AND METHODS Isolated CD8+ T cells from CB and PB were stimulated antigen independently with anti‐CD3/CD28 stimulator beads or in an antigen‐dependent manner with artificial antigen‐presenting cells loaded with the HLA‐A*02:01‐restricted peptide of tumor‐associated melanoma antigen recognized by T cells 1 (MART1). CB and PB T cells cultured in the presence of interleukin (IL)‐7, IL‐15, IL‐12, and IL‐21 were characterized for T‐cell phenotype and specificity, that is, by CD107a, interferon‐γ, tumor necrosis factor‐α, and IL‐2 expression. RESULTS After antigen‐independent stimulation, activated CD8+ CB T cells exhibited stronger proliferation and function than those from PB. After antigenic stimulation, MART1‐reactive CB T cells were naïve (CD45RA+CCR7+), cytotoxic, and highly variable in expressing homing marker CD62L. Addition of IL‐21 resulted in increased T‐cell proliferation, whereas supplementation with IL‐12 decreased IL‐21–induced expansion, but increased the functionality and cytotoxicity of CB and PB T cells. CONCLUSION MART1‐reactive CB T cells with a more naïve phenotype and improved properties for homing can be generated. The results contribute to better understanding the effects on GVHD and graft versus tumor.

‘Off-the-shelf’ allogeneic CAR T cells: development and challenges

“…The use of UCB-derived CAR-T cell transplantation can be associated with reduced incidence and severity of GVHD, which allows less stringent restrictions on the number of Hla disparities 9 . Indeed, T cells derived from UCB have a unique antigen-naive status that may be related to the decreased alloreactivity of UCB grafts 10 . Furthermore, UCB T cells are also characterized by impaired nuclear factor of activated T cells (NFAT) signalling and reduced reactivity 11 , which may also explain the decreased risk of GVHD.…”

MicroRNA-29 specifies age-related differences in the CD8+ T cell immune response

“…Inhibition of miR-29 in naive adult cells was sufficient to increase expression of the activation markers CD69, CD25 and CD44, levels of effector cytokines, and proliferation (Figures 6E, S6E, and S6F). Thus, miR-29 modulation in human naive adult cells reprograms fundamental attributes of CD8+ T cells, resulting in a more cytotoxic state typical of newborns (Kwoczek et al, 2018;Jacks et al, 2018). Conversely, when we delivered miR-29 to naive human cord cells, levels of activation markers and effector cytokines were decreased, along with a reduction in proliferation (Figures 6F, S6E, and S6F).…”

Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

“…In addition to the above cytokines, the IL-7 signal is a potent stimulator of T cell proliferation and expansion [61], and the expression of IL-7Rα improves the function and efficacy of CAR T cells in solid tumor environments. As reported, CAR T cells co-expressing an IL-7 cytokine receptor (C7R) had increased T cell proliferation and survival and enhanced anti-tumor activity in metastatic neuroblastoma and orthotopic glioblastoma xenograft models [62].…”